This Small Business Innovation Research (SBIR) Phase I project will develop a new platform technology to exploit previously inaccessible microbial diversity to discover novel broad-spectrum antibiotics. The project focuses on symbioses between marine invertebrates and microorganisms known to be rich sources of novel bioactive compounds with potential therapeutic value. Microbial symbionts have long been suspected to be the actual producers of such compounds. They, and other microorganisms in general, remain largely unexplored because over 99% of them cannot be cultivated in the laboratory. Recovery of cultivable microorganisms from the sea is especially poor (0.1 to 0.01%) making the ?missing? marine species particularly attractive. The company employs a radically new method for in situ cultivation of previously uncultured microorganisms that significantly raises the cultivability of environmental bacteria, from<1% using traditional technologies to>20%. In Phase I, the company will adopt and optimize this method to access microorganisms specifically from marine symbioses, isolate novel microbial species from marine sponges and corals, and explore their antimicrobial properties. The principle intellectual merit and innovation of this proposal is in focusing on an essentially novel source of antimicrobials, microbes living in association with marine invertebrates, and the use of a novel method to grow these microbes. The broader impact/commercial potential of this project stems from an increasing need for new antibiotics with new modes of action that are not susceptible to current resistance mechanisms. Agencies such as the Antimicrobial Availability Task Force of the Infectious Diseases Society of America and the World Health Organization have publicized the urgency of the resistance problem and the lack of forthcoming antibiotics in development. The multiple antibiotic-resistant bacteria are the exact pathogens that the company is targeting. Although big Pharma has largely abandoned their antibiotic discovery programs, they remain interested in acquiring new viable antibiotics. The global market for antibiotics is over $25 billion. Top earners, such as Levaquin (Floxin), Zosyn, and Augmentin have 2008 sales over $1 billion, with significant resistance already observed to all three. There is also an acute, unmet need and market even for narrow-spectrum antibiotics. Their commercial value and societal importance cannot be overstated. Of particular importance is that the proposed research will not only lead to a selection of novel antimicrobials, but to a new technology platform forming a whole new pipeline of new therapeutics.